HIV-1 associated neurologic disease is believed to be the result of a chronic inflammatory state, in which[unreadable] soluble neurotoxic molecules, of both viral and cellular origin, act to cause neuronal injury and dysfunction.[unreadable] We hypothesize that HIV-1 neurotoxicity is opposed by a number of endogenous pathways and mediators,[unreadable] which serve to protect neurons. For example, neurotrophins can augment neuronal survival and function[unreadable] through the activation of specific receptors (Trk receptors) and subsequent initiation of signaling cascades.[unreadable] We therefore propose to study endogenous neuroprotective pathways that may provide us with new[unreadable] therapeutic strategies for neuroAIDS. This will be achieved through two specific aims. In Aim 1, experiments[unreadable] will focus on signaling pathways associated with neurotrophin receptor activation, including analyses of the[unreadable] neuroprotective effects of inhibitors of mixed lineage kinases (MLK)-3, p38 kinase and c-Jun NH2 terminal[unreadable] kinases (JNK), as well as peptidomimetic Trk ligands. Effects on the survival and function of neurons[unreadable] exposed to candidate HIV-1 neurotoxins will be evaluated, as will effects on monocyte/microglial activation.[unreadable] In the second aim, we will evaluate the cell signaling events that are modulated in response to the inhibition[unreadable] of MLK-3, using both pharmacological and genetic approaches. These experiments will take advantage of[unreadable] available dominant negative mutants and MLK-3 knockout mice (to genetically target MLK-3), as well as[unreadable] extant pharmacologic compounds and new, highly specific MLK-3 blockers that will be developed by our[unreadable] commercial partner. Collectively, these investigations will identify novel neuroprotective strategies that may[unreadable] enhance neuronal function and survival in neuroAIDS. Results from these studies will be correlated with[unreadable] intracellular signaling events that occur in response to drug treatment, in order to identify new therapeutic[unreadable] targets..